The complications of arteriosclerosis in the United States account for about one half of all deaths. Three fourths of arteriosclerosis-related deaths are the result of coronary artery disease (CAD), also termed ischemic heart disease. Arteriosclerosis-related diseases are also the leading cause of permanent disability and account for more hospitalization than any other illness. Atherosclerosis or the development of atheromatous plaques in large and medium-sized arteries, is the most common form of arteriosclerosis. Preventing formation or growth of atherosclerotic plaques is widely regarded as a promising approach to the primary and secondary prevention of CAD.
The primary initiating factors in the formation of atheromatous plaques are the recruitment of monocytes into the vascular wall and the proliferation and migration of smooth muscle cells from the media to the intima of the arterial wall. Presumably, these events are accelerated by the deposition of cholesterol and other lipids carried in by the plasma lipoproteins, particularly LDL. The atherogenic process, at first, produces simple atheromatous plaques, as the monocytes differentiate into macrophages and they and the smooth muscle cells take up lipids. Later, lipids, collagen, elastic fibers and proteoglycans are deposited in the extracellular space. Hemorrhage, necrosis, and calcification occur at still later stages. It has been suggested that the vessel wall thickness is a conserved parameter, homeostatically regulated by the balance between cell renewal and cell death. Thus, as vascular smooth muscle proliferation increases in response to specific physiologic signals, apoptosis (or programmed cell death) increases in compensation to conserve total cell mass.
If pathophysiological signals for proliferation continue to be exerted, for example, when hyperlipidemia is chronically maintained, mechanisms to limit the expansion of cell mass in the arterial wall may become overwhelmed. The end result is that the vessel wall thickness expands and the lumen of the artery narrows, resulting in the secondary complications of reduced blood flow to the tissues and organs downstream of the stenotic vessel. A reduction in cell proliferation or the induction of apoptosis in this early stage of development of the atherosclerotic lesion may therefore be beneficial in limiting the increased population of macrophages and smooth muscle cells or other cells. However, in the later stage of an atherosclerotic lesion, factors promoting cell death may destabilize the plaque and cause the release of pro-thrombotic material into the extracellular space. This in turn, may enhance the tendency toward platelet aggregation and formation of detrimental clots.
Therefore, cell death may have anti- or pro-atherogenic effects depending on the type and evolution of the atherogenic lesion.
Similarly, the expanded population of vascular cells after interventions intended to increase coronary perfusion, such as but not limited to angioplasty, may represent an imbalance of cell proliferation over cell death, resulting in restenosis of the vessel.
The stimulated platelet synthesizes thromboxane (TX) A.sub.2, which can aggregate other platelets and constrict vascular smooth muscle. These platelets also release ADP and serotonin, which likewise serve to recruit other platelets. Thrombin generated in the vicinity of a platelet plug or thrombus, as well as platelet endoperoxides, can act as stimuli for prostacyclin (PGI.sub.2) production in the vasculature. Since PGI.sub.2 has anti-aggregating effects on platelets, there emerged a therapeutic strategy to balance PGI.sub.2 and TXA.sub.2 production in an attempt to regulate aggregability of platelets in vivo. An ideal therapeutic situation is one in which TXA.sub.2 production is abolished but PGI.sub.2 synthesis continues unabated or is stimulated. This led to development of specific thromboxane synthetase inhibitors or prostacyclin synthetase stimulators. For example, aspirin, a non-steroidal anti-inflammatory agent NSAID) and an antithrombotic agent irreversibly acetylates platelet cyclooxygenase and reverses the platelet aggregation, although cyclooxygenase in vascular tissues has been found to be 20-to 40- fold less sensitive to aspirin inactivation than the cyclooxygenase in platelets. Since a balance between PGI.sub.2 and TXA.sub.2 production is important, its manipulation by pharmacologic agents, including, but not limited to, other NSAIDs (e.g., ibuprofen sulindac, sulindac sulfide, sulindac sulfone, flurbiprofen, indomethacin, aspirin, naproxen, meclafenamic acid, or piroxicam) has been used extensively in retarding a thrombotic diathesis. However, heretofore, the use of NSAIDs in the control of cell death, cell differentiation, migration, or proliferation in an animal model of human atherosclerosis or restenosis has not been identified, much less considered as therapeutic interventions for the prevention and treatment of arterial lesions in various forms of coronary artery disease. Heretofore, the use of NSAIDs in atherosclerosis other than to interfere with thrombotic or platelet aggregatory mechanisms has not been identified, much less considered.